This is a proposal to renew RO1 MH053608, which supports our studies of the immediate early gene Arc. Arc is a synaptic protein that is required for animals to learn and store information1. Arc associates with endocytic proteins to regulate glutamate receptor trafficking and thereby control the strength of excitatory synapses2,3. Arc-dependent mechanisms play an important role in synaptic plasticity of learning, but are also implicated in diseases of cognition including fragile X mental retardation syndrome4-6, Angelman syndrome7, Alzheimer's disease8,9 and schizophrenia 10,11. The association of Arc with synaptic pathophysiology drives a need for deep understanding of Arc's function. This has been challenging because Arc is a single copy gene without discernable family members or recognizable functional domains. To address this challenge, we have focused recent efforts on defining the structure of Arc, and have made break through discoveries that reveal the basis of Arc association with synaptic proteins important for trafficking and synaptic turnover. We have also identified protein interactions that support a role for Arc in control of PI3 Kinase, AKT and mTORC. Studies will evaluate hypotheses of Arc functions that derive from new structural information and that are central to its action in synaptic plasticity and disease.